Abstract

Herein, we systematically investigate phospholipid-subclass-specific alterations in the partitioning of both cationic and anionic amphiphiles to identify the importance of ester, ether and vinyl ether linkages at the sn-1 position of phospholipids in the partitioning of charged amphiphiles. The results demonstrated that the membrane–water partition coefficient of a prototypic cationic amphiphile (i.e. 3,3´-dipropylthiadicarbocyanine iodide) was approximately 2.5 times higher in membranes comprised of plasmenylcholine in comparison with membranes comprised of either phosphatidylcholine or plasmanylcholine. In striking contrast, the membrane–water partition coefficient of a prototypic anionic amphiphile [i.e. bis-(1,3-dibutylbarbituric acid)trimethine oxonol] in membranes comprised of plasmenylcholine was ≈ 2.5 times lower than that manifest in membranes comprised of phosphatidylcholine or plasmanylcholine. Utilizing these experimentally determined partition coefficients,the relative membrane dipole potential of membranes comprised of plasmenylcholine was calculated and found to be ≈ 25 mV lower than in membranes comprised of phosphatidylcholine or plasmanylcholine. This lower membrane dipole potential in membranes comprised of plasmenylcholine is equivalent to the membrane potential induced by incorporation of ≈ 25 mol% of anionic phospholipids in membranes comprised of phosphatidylcholine. Collectively, these results demonstrate that phospholipid-subclass-specific differences in the membrane dipole potential contribute to alterations in the partitioning of lipophilic ions in membrane bilayers comprised of distinct phospholipid subclasses. Moreover, they suggest that these physicochemical differences can be exploited to facilitate the targeting of charged lipophilic drugs to specific cells and subcellular membrane compartments.